The invention relates generally to methods of identification of cell types on the basis of identification of specific targets, and more specifically to methods of identifying pancreatic cancer cells on the basis of the expression of a particular combination of specific targets.
The targeting of imaging agents or therapeutic agents to molecular targets on the surface of particular cell types holds considerable promise as a research, diagnostic and therapeutic strategy. Cell surface molecules are often favored because their structural diversity and because agents that target cell surface molecules do not need to cross the plasma membrane to reach their targets. Many targeting agents contain one or more moieties capable of specifically binding a single cell surface protein. Such agents include small molecules and monoclonal antibodies. There have been successes using this approach. In one example, a series of RGD-peptide based ligands coupled with a variety of proteins, small molecules, nucleic acids and radiotracers were developed to deliver therapeutics to tumor vasculature (see reference 18). The 18F-Galacto-RGD ligand was tested in humans and showed desirable pharmacokinetics and good visualization of αvβ3-integrin expression under PET scan (see references 19 and 20). Additionally, radiolabeled monoclonal antibodies that target cell surface antigens were approved as a treatment of B-cell non-Hodgkin's lymphoma (see reference 21). However, while such monospecific (also termed monomeric or monovalent) agents have demonstrated some utility in targeting and identifying some tumors, their use is limited the rare instance in which a target is expressed at a high level on tumor relative to normal tissue. Moreover, agents capable of binding only a single cell surface target might not be specific enough to differentiate one cell type from another (in one nonlimiting example, differentiation of a tumor cell from a noncancerous cell). As a result, some monospecific agents used as therapeutics often cause substantial side effects. Similarly, only a small proportion of cell surface targets are overexpressed in solid tumors relative to normal tissues. Therefore, monospecific ligands are useful in only a small proportion of the potential cell surface targets on solid tumors.
A multispecific (also termed multimeric or multivalent) ligand, on the other hand, has multiple binding specificities per ligand. Because a multispecific ligand can bind multiple surface targets on a cell, it has a greater overall affinity and avidity to cells expressing a particular combination of targets with minimal binding to cells that express only some or none of the targets. Such a ligand would also be able to select between very similar cell types, indicating new subpopulations of cells. This would have important implications in the fields of research, diagnostics and therapeutics. See references 11, 22-24. Multispecific ligands, then, have great potential. However, the development of such ligands is has been slowed by the difficulty of identifying combinations of targets that, when concurrently expressed, identify a particular cell type. If multispecific ligands are to become a viable treatment option, methods that identify particular cell types using combinations of targets are necessary.
So as to reduce the complexity and length of the Detailed Specification, and to fully establish the state of the art in certain areas of technology, Applicants herein expressly incorporate by reference all of the following materials identified in each numbered paragraph below. The incorporated materials are not necessarily “prior art” and Applicants expressly reserve the right to swear behind any of the incorporated materials.                1. Jemal A et al, Cancer Statistics, CA Cancer J Clin 56, 106-130 (March/April, 2006).        2. Hale G, Therapeutic antibodies—Delivering the promise?, Adv Drug Deliv Rev, 58 633-639 (May, 2006).        3. Pegram M D et al, Targeted therapy: wave of the future. J Clin Oncol 23 1776-1781 (2005).        4. Reichert J M et al, Monoclonal antibody successes in the clinic. Nat Biotechnol 23 1073-1078 (2005)        5. Richter M and H Zhang, Receptor-targeted cancer therapy. DNA Cell Biol 24 271-282 (2005)        6. 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Applicants believe that the material incorporated above is “non-essential” in accordance with 37 CFR 1.57, because it is referred to for purposes of indicating the background of the invention or illustrating the state of the art. However, if the Examiner believes that any of the above-incorporated material constitutes “essential material” within the meaning of 37 CFR 1.57(c)(1)-(3), applicants will amend the specification to expressly recite the essential material that is incorporated by reference as allowed by the applicable rules.